Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation

Alejo, Alı́; Ruiz-Argüello, M. Begoña; Pontejo, Sergio M.; Marco, Maria del Mar Fernández de; Saraiva, Margarida; Hernáez, Bruno; Alcamı́, Antonio

doi:10.1038/s41467-018-04098-8

Cited by 31 publications

(36 citation statements)

References 75 publications

(108 reference statements)

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“…We have recently demonstrated that CrmD is an essential virulence factor for ECTV, which causes mousepox, a smallpox-like disease in mouse. In addition, we showed that both CrmD activities, anti-TNF and antichemokine, are required for a successful evasion of the host immune response by ECTV (27).…”

mentioning

confidence: 90%

Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

Pontejo

Sánchez

Ruiz-Argüello

et al. 2019

Journal of Biological Chemistry

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Edited by Charles E. Samuel This work was supported by Spanish Ministry of Economy and Competitiveness Grants SAF2012-38957 and SAF2015-67485-R and the European Union (European Regional Development Fund). S. M. Pontejo, C. Sanchez, and A. Alcami are inventors of a patent application on the potential use of the variant form of etanercept, but there is no company involved or development of this reagent as a drug so far. This article was selected as one of our Editors' Picks. This article contains Fig. S1 and Table S1.

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confidence: 90%

Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

Pontejo

Sánchez

Ruiz-Argüello

et al. 2019

Journal of Biological Chemistry

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“…In this work, we aimed to investigate the presence of these cells in different clinical forms of dengue infection. Because IL10 + Th1 may also express other cytokines besides IL10 and IFNγ, 32 we decided also to investigate the production of tumor necrosis factor (TNF), a cytokine that possesses anti‐viral properties 33 and has also been found in a subpopulation of T‐cells producing IFNγ simultaneously during DENV infections 30,31 . Therefore, in this work, we evaluated dengue patients for the presence of DENV‐specific T‐cells producing IFNγ, TNF and/or IL10 at defervescence (critical) and convalescence phases of infection.…”

Section: Introductionmentioning

confidence: 99%

T‐cells producing multiple combinations of IFNγ, TNF and IL10 are associated with mild forms of dengue infection

et al. 2020

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Multifunctional interleukin 10 (IL10) + Th1 cells have been implicated in favorable evolution of many infectious diseases, promoting an efficacious immune response while limiting immunopathology. Here, we investigated the presence of multifunctional CD4 + and CD8 + T-cells that expressed interferon gamma (IFNc), IL10 and tumor necrosis factor (TNF), or its combinations during dengue infection. Peripheral blood mononuclear cells (PBMCs) from outpatients with dengue (mild dengue forms) and hospitalized patients (or patients with dengue with warning signs and severe dengue) were cultured in the presence of envelope (ENV) or NS3 peptide libraries of DENV during critical (hospitalization period) and convalescence phases. The production of IFNc, IL10 and TNF by CD4 + and CD8 + T-cells was assessed by flow cytometry. Our data show that patients with mild dengue, when compared with patients with dengue with warning signs and severe dengue, presented higher frequencies of multifunctional T-cells like NS3-specific IFNc/IL10-producing CD4 + Tcells in critical phase and NS3-and ENV-specific CD8 + T-cells producing IFNc/IL10. In addition, NS3-specific CD8 + T-cells producing high levels of IFNc/TNF and IFNc/TNF/IL10 were also observed in the mild dengue group. We observed that multifunctional T-cells produced higher levels of cytokines as measured by intracellular content when compared with single producer T-cells. Importantly, multifunctional CD4 + and CD8 + T-cells producing IFNc, TNF and IL10 simultaneously displayed positive correlation with platelet levels, suggesting a protective role of this population. The presence of IL10 + Th1 and IL10 + Tc1 multifunctional cells was associated with mild dengue presentation, suggesting that these cells play a role in clinical evolution of dengue infection.

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“…Blockade of TNF by soluble TNF inhibitors including receptors and different monoclonal antibodies is an effective therapeutic strategy widely used for the treatment of RA and other inflammatory conditions [39]. During viral infection, concomitant blockade of both TNF and a reduced set of chemokines by a single secreted protein was found to completely abrogate local inflammation in the mousepox intradermal infection model, effectively ablating the host response to produce a lethal infection [19]. Strikingly, both TNF and chemokine inhibition were found to be required for this effect, which may reflect the local crosstalk between both signaling pathways as well as the cell types that produce and respond to them.…”

Section: Discussionmentioning

confidence: 99%

“…While the SECRET domain can be found independently in three different viral proteins, it was shown to act in concert with the TNF-binding moieties in CrmD and CrmB, which are thus effectively bispecific cytokine inhibitors. Importantly, in vivo experiments using the mousepox model showed that both TNF-and CK-blocking activities are important determinants of virulence and have complementary roles in the control of local inflammation during infection [19].…”

Section: Introductionmentioning

confidence: 99%

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Alejo

Sánchez

Amu

et al. 2019

JCM

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The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein.A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.

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Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation

Cited by 31 publications

References 75 publications

Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

T‐cells producing multiple combinations of IFNγ, TNF and IL10 are associated with mild forms of dengue infection

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

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